TGM2 Activates the ERK Signaling Pathway to Disrupt Intestinal Barrier Function and Aggravate Colitis

Background: PANoptosis-related transcriptional programs may contribute to pediatric ulcerative colitis (UC), but the genes most consistently associated with disease activity and epithelial injury remain uncertain. Methods: Public transcriptomic cohorts were integrated with machine-learning feature selection, treatment-response analyses, immune cell deconvolution, molecular clustering, and two-sample Mendelian randomization (MR). Transglutaminase 2 (TGM2) expression was examined in colonic specimens from six pediatric patients with UC and six controls. TGM2 knockdown was evaluated in lipopolysaccharide-stimulated HT29 cells using inflammatory gene analysis, tight junction protein measurements, RNA sequencing, and MAPK signaling assays. Results: A total of 17 differentially expressed PANoptosis-related genes were identified, and CCL2, JAK3, and TGM2 were prioritized as candidate genes. In the external GSE126124 cohort, TGM2 yielded an area under the curve of 0.918 in colonic tissue and 0.744 in peripheral blood. TGM2 expression was associated with disease activity, inflammatory cell estimates, barrier-related gene expression, and treatment response. Six single-nucleotide polymorphisms (SNPs) were included in the MR analysis. The inverse-variance weighted estimate was significant (odds ratio 1.486, 95% confidence interval 1.055–2.092; p = 0.023), whereas the other four methods were not significant. In LPS-stimulated HT29 cells, TGM2 knockdown was accompanied by lower TNF-α, IL-1β, and IL-6 expression, increased ZO-1, Occludin, and Claudin-3 abundance, and reduced ERK phosphorylation; substantial changes in JNK or p38 phosphorylation were not detected. Conclusion: TGM2 was identified as a candidate through PANoptosis-related bioinformatic screening. TGM2 expression was associated with pediatric UC activity and treatment response, whereas TGM2 knockdown was associated with reduced inflammatory gene expression, increased tight junction protein abundance, and lower ERK phosphorylation in LPS-stimulated HT29 cells. Functional involvement of TGM2 in PANoptosis and its mechanistic position within ERK signaling require further validation.